Our New Trends in Neuroscience Paper:

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) was recently revealed to be a synaptic player during plasticity events in addition to its well-established role as a general controlling factor in cell proliferation and neuronal growth during development. Alterations of these direct actions of PTEN at synapses may lead to synaptic dysfunction with behavioral and cognitive consequences. A recent paradigmatic example of this situation, Alzheimer's disease (AD), is associated with excessive recruitment of PTEN into synapses leading to pathological synaptic depression. By contrast, some forms of autism are characterized by failure to weaken synaptic connections, which may be related to insufficient PTEN signaling. Understanding the modulation of synaptic function by PTEN in these pathologies may contribute to the development of new therapies.

Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN)-Mediated Synaptic Dysfunction in Alzheimer's Disease and Autism. (A) The presence of amyloid β induces exaggerated synaptic recruitment of PTEN. The triggering mechanism remains unknown but requires NMDA receptor activation and relies on PDZ-dependent interactions, similar to physiological long-term depression (LTD). The sustained recruitment of PTEN at the postsynaptic membrane leads to excessive removal of AMPA receptors, skewing synaptic plasticity towards depression and producing chronic synaptic weakening. (B) In some forms of autism, PTEN loss of function produces excessive neuronal proliferation and synaptic connectivity during development. In addition, these synapses will fail to be appropriately depressed during plasticity events because of insufficient (or lack of) PTEN activity. This will result in synaptic hyperactivity, which will eventually exacerbate the hyperconnectivity and hyperexcitability phenotypes that started during brain development.

Our New Nature Neuroscience Paper:

Dyshomeostasis of amyloid-β peptide (Aβ) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. Aβ appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer's disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aβ-induced depression. Mechanistically, Aβ triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aβ-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aβ-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aβ signaling.

This new book contains a vast amount of information regarding traditional and modern strategies aimed at enhancing cognitive function, both in animals and humans. The editors made an effort to make this book accessible to the general public, although some of the chapters may be more scientifically orientated than others. Nevertheless, the general goal of this book is to bring together the bulk of information available in this field, in the hope that this will eventually help scientists to develop new, more efficient approaches to treat cognitive impairment.

News

Neurons communicate with one another by synaptic connections, where information is exchanged from one neuron to its neighbor. These connections are not static, but are continuously modulated in response to the ongoing activity (or experience) of the neuron. This process, known as synaptic plasticity, is a fundamental mechanism for learning and memory in humans as in all animals. In fact, we now know that alterations in synaptic plasticity are responsible for memory impairment in cognitive disorders such as Alzheimer’s disease. Nevertheless, the mechanisms by which these alterations take place are still starting to be uncovered.

This new research work, published in Nature Neuroscience reports that in Alzheimer’s disease, synaptic plasticity is altered by a protein originally described as a tumor suppressor: PTEN. In 2010, the research group of Dr. Esteban discovered that PTEN is recruited to synapses during normal (physiological) synaptic plasticity. This new investigation by Drs. Knafo, Venero and Esteban, now indicates that this mechanism runs uncontrolled during Alzheimer’s disease. One of the pathological agents of the disease, the beta-amyloid, drives PTEN into synapses excessively, unbalancing the mechanisms for synaptic plasticity and impairing memory formation.

An important aspect of this study is that it also describes how PTEN is recruited to synapses in response to beta-amyloid, and proposes a strategy to prevent it. Using a mouse model of Alzheimer’s disease, the investigators developed a molecular tool to shield synapses from the recruitment of PTEN. With this tool, neurons are rendered resistant to beta-amyloid, and Alzheimer’s mice preserve their memory.

Although this is basic research using animal models, these studies contribute to dissect the mechanisms that control our cognitive function, and orient us towards potential therapeutic avenues for mental diseases where these mechanisms are deficient.

From the web: "A recent study in PLoS Biologyshould give hope to the forgetful. A collaborative research group in Europe, spanning Spain, Switzerland and Denmark, developed a small protein called FGL that enhances memory formation and learning in rats, and now they have some explanation as to why. The study’s authors, led by Shira Knafo, César Venero and José Esteban, attribute the improvement from FGL to better connections—and ability to strengthen those connections—between neurons. This knowledge may eventually improve treatment of some disorders, as the authors explain that these “mechanisms are thought to be responsible for multiple cognitive deficits, such as autism and Alzheimer’s disease”

How it might work

In their most recent article, the authors suggest that FGL improves the brain's ability to modify the connections between neurons, the cells that are the building blocks of the brain. When examining neurons that had been treated with FGL, Knafo, Venero and Esteban found that they had higher levels of a receptor, AMPA, critical for modifying neuronal connections.

As the authors write, "The human brain contains trillions of neuronal connections, called synapses, whose pattern of activity controls all our cognitive functions. These synaptic connections are dynamic and constantly changing in their strength and properties, and this process of synaptic plasticity is essential for learning and memory. In this study, we show that synapses can be made more plastic using a small protein."

Many neuroscientists consider understanding plasticity the Holy Grail for learning and memory; once we understand plasticity, we will understand how the brain learns.